Project summary: Sensitive periods denote developmental time windows of plasticity during which the anatomy and function of the nervous system becomes hard-wired. Frequently, these windows represent periods in which the refinement of brain circuitry and function is particularly susceptible to changes in ongoing activity. A classic example is the visual system where transient developmental monocular deprivation can permanently impair acuity in the deprived eye. This impairment in function persists even after deprived eye vision is restored as the balance of thalamocortical inputs representing the closed and open eyes is shifted in a competitive activity- dependent manner. While sensitive periods regulate circuit refinement in sensory cortices, it is unclear whether they also govern maturation of circuitry in the prefrontal cortex (PFC), an associative cortical area that supports higher cognitive functioning. Here, we propose to perturb the maturation of medial PFC circuitry by transiently inhibiting thalamo-mPFC projections in the mouse during adolescence. We hypothesize that this will lead to persistent deficits in cognitive behaviors. Our preliminary data give strong support for this hypothesis as inhibition of the medio-dorsal thalamus during a broad postnatal developmental time window leads to persistent deficits in the acquisition of a mPFC dependent working memory task. In this R21 application we will first narrow down the sensitive time window involved by inhibiting thalamo-mPFC projections during three different time windows ranging from early adolescence to early adulthood. We hypothesize that inhibition during one or both adolescent time windows will affect adult cognitive performance, whereas inhibition during early adulthood has no lasting consequences for task performance. Second, using in vivo physiology we will simultaneously record from several nodes of mPFC circuitry including mPFC, MD, and ventral hippocampus during adult task performance. We will further include the orbito-frontal cortex (OFC) in this analysis, as its inputs were not inhibited during adolescence. We hypothesize that adolescent inhibition of thalamo-mPFC projections will lead to persistent changes in mPFC circuit function that may explain deficits in the behavioral performance. Aim 1. To determine whether transient inhibition of thalamo-mPFC projections during adolescence leads to persistent deficits in cognition Aim 2: To determine whether transient inhibition of thalamo-mPFC projections during adolescence leads to persistent abnormalities in mPFC circuit function Studying adolescent periods of PFC circuit maturation will be important for understanding psychiatric disorders with a neurodevelopmental origin and altered PFC function. Notably, in schizophrenia, high-risk adolescent subjects display decreased thalamo-prefrontal connectivity, which has been associated with cognitive deficits and illness conversion.